Imaging

A longitudinal study examining three RDoC constructs in adolescents with non-suicidal self-injury

Principal Investigator:

Kathryn Cullen, MD (Department of Psychiatry)

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Collaborators:

Bonnie Klimes-Dougan, PhD (Department of Psychology), Kelvin Lim, MD (Department of Psychiatry), Karina Quevedo, PhD (Department of Psychiatry), Katie Thomas, PhD (Institute of Child Development)

Abstract:

Non-Suicidal Self Injury (NSSI) is a common clinical problem that cuts across many different psychiatric diagnoses, leads to severe negative outcomes, and has limited treatment options. Advancement of new interventions for NSSI is hindered by a lack of knowledge about its neural mechanisms. NSSI usually emerges during adolescence, a time period notable for significant developmental changes in brain and behavior. Characterizing the developmental trajectories of key aberrant neural systems would enhance our understanding of the pathophysiology of NSSI. The current study will be instrumental in guiding foundational knowledge necessary for creating targeted early interventions for adolescents with NSSI that are designed to promote healthy neurodevelopment.

An open-label, single-arm, multicenter study of intracerebral administration of adeno-associated viral vectors serotype rh10 carrying the human N-sulfoglucosamine sulfohydrolase (SGSH) cDNA for the treatment of mucopolysaccharidosis type IIIA

Principal Investigator:

Julie Eisengart, PhD, LP (Department of Pediatrics)

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Collaborators:

Chester B. Whitley PhD, MD (Department of Pediatrics), Amy Esler, PhD (Department of Pediatrics)

Abstract:

Mucopolysaccharidosis IIIA (MPS IIIA), also known as Sanfilippo Syndrome Type A, is a rare pediatric disease that is a uniformly fatal childhood disease. This autosomal recessive lysosomal storage disease is caused by a missing or dysfunctional catabolic protein, leading to the subsequent accumulation of substrates in the cell, resulting in very severe cellular and organ dysfunctions, particularly prominent in the central nervous system. Severe behavior dysregulation, sleep disturbance, and cognitive decline are the phenotypic hallmarks of MPS IIIA.

MPS IIIA has an incidence of 0.44-1.16 per 100,000 births and is caused by autosomal recessive genetic defects of the N-sulfoglucosamine sulfohydrolase (SGSH) gene localized to 17q25.3. SGSH is a secreted enzyme involved in the stepwise degradation of heparan sulfate (HS). A  deficiency in SGSH leads to an accumulation of HS in cells and affects cellular functioning  including lysosomal clearance. Currently, there ae no disease-modifying treatment(s) available or MPS IIIA.

The treatment proposed here, using Lysogene's in-vivo gene therapy LYS-SAF302 product (adeno-associated viral vector serotype rh.10 canying the human N-sulfoglucosamine sulfohydrolase cDNA)  consists of an intracerebral multi-injection site administration performed in a single operation.  It is hoped that treated patients would maintain existing cognitive and neurodevelopmental capabilities and possibly would acquire new skills.

Effects of single-session transcranial direct current stimulation in children with cerebral palsy

Principal Investigator:

Bernadette Gillick, PhD, MSPT, PT (Department of Rehabilitative Medicine)

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Abstract:

Neurorehabilitation in cases of hemiparesis has primarily focused on intensive motor training to encourage use of the affected extremities in an effort to produce use-dependent neuroplasticity in the brain. Such interventions are effective, but require a burdensome amount of time, 60-90 hours per week, for both the child and therapist. Furthermore, some children do not respond at all to such training.

Neuromodulation is a relatively new field that aims to influence the brain’s neuronal activity through direct application of magnetic (TMS) or electric (tDCS) energy. It is thought the combination of neuromodulation and motor training may reduce the dosage of training needed, and would promote recovery to a greater extent for more individuals. Indeed, previous work in adult stroke demonstrate a benefit of combining repetitive TMS (rTMS) and tDCS with motor training, compared to training alone. These types of synergistic interventions are just beginning to be used in children with UCP, with some preliminary data showing potential benefit.

This study aims to offer insight into the mechanisms of tDCS and lead the field toward a better understanding of how tDCS be implemented in a neurorehabilitation setting for both children and potentially adults.

Long-term follow-up of term survivors of hypoxic-ischemic encephalopathy: an evaluation of brain function and structure

Principal Investigator:

Katie Pfister, MD (Pediatrics, Division of Neonatology)

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Collaborators:

Elizabeth Zorn, MD (Pediatrics: Division of Neonatology), Christopher Boys, PhD, LP (Department of Pediatrics), Katie Thomas, PhD (Institute of Child Development)

Abstract:

A prospective observational cohort study design will be used to determine whether survivors of HIE who were treated with therapeutic hypothermia have deficits in memory or executive function at age 4-5 years, and whether there are observable changes in brain structure or connectivity. MRI with diffusion tensor imaging will be used to assess brain volumes, structure, and white matter connectivity. Behavioral assessments (WPPSI-IV and NEPSY-II) and parental questionnaires (BRIEF-P) will be used to assess overall intellectual function, executive function, and memory.

Longitudinal assessment of asymptomatic congenital CMV infection in Minnesota infants identified by universal screening: what is risk of sequelae?

Principal Investigator:

Mark Schleiss, MD (Department of Pediatrics)

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Collaborators:

Jed Elison, PhD (Institute of Child Development), Igor Nestrasil, MD, PhD (Department of Pediatrics), Erin Osterholm, MD (Department of Pediatrics)

Abstract:

Symptomatic congenital CMV (cCMV) infections are commonly encountered in clinical practice, affecting approximately 0.65% of all newborns. Such infections - in symptomatic newborns - carry a substantial risk for long-term neurodevelopmental sequelae including developmental delay, mental retardation, seizure disorders, cerebral palsy, and sensorineural hearing loss. Nucleoside antiviral therapy is associated with only modest improvements in audiological and neurodevelopmental outcomes. It is much less clear how to manage infants identified with asymptomatic cCMV infection. These infants have in the past essentially escaped clinical recognition, precisely because these children are asymptomatic at birth, and there is no universal newborn cCMV screen. However, the landscape of cCMV screening is rapidly evolving, and there is increasing interest in implementation of universal cCMV screening programs.  In spite of recent progress, universal newborn screening for congenital CMV in many ways remains an area of scientific uncertainty. The optimal screening methodology remains uncertain. We don’t know if asymptomatic infants should undergo full laboratory and neuroimaging evaluations, or whether treatment of infants with asymptomatic congenital CMV with antivirals should be considered. Our proposal will conduct neurocognitive and neuroimaging studies in asymptomatic infants identified with congenital CMV infection in the context of a universal screening program to address these important areas of knowledge deficit. 

Longitudinal studies in MPS disorders: a multicenter study of the lysosomal disease network, longitudinal studies of brain structure and function in MPS disorders

Principal Investigator:

Chester B. Whitley, PhD, MD (Department of Pediatrics)

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Abstract:

The purpose of this study is to examine the changes in the central nervous system over time in patients with MPS I, II, IV, VI, and VII in both structure and function. We have determined that localization in the brain of abnormal cognitive and behavioral attributes varies by the type of MPS disorder. We will be examining how changes in the brain over time reflects the natural course of the disease or the effects of past or currently administered treatment such as hematopoietic cell transplant, systemic enzyme replacement or intrathecal enzyme replacement.

We hypothesize that specific and localized neuroimaging, neuropsychological and neurobehavioral findings and their relationship will be distinct for each MPS disorder. Further, without appropriate treatment, functions will decline and structure will change over time specific to each disease and stage of disease. We hypothesize that treatments such as ERT, HCT, HCT+ERT, and palliative and rehabilitation therapies, will differentially affect brain structure, functions and quality of life. Finally, we hypothesize that for each MPS type, variables such as age at first treatment, severity of disease, medical events related and unrelated to the disease, mutation, family and environmental factors, sensory abnormalities, and sociodemographic variables will influence brain functional and structural outcomes as well as quality-of-life.

Mapping the Human Connectome During Typical Development

Principal Investigator:

Kathleen Thomas, PhD (Institute of Child Development), Essa Yacoub, PhD (Center for Magnetic Resonance Imaging)

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Abstract:

The major technological and analytical advances in adult human brain imaging achieved as part of the Human Connectome Projects (HCP) have allowed unprecedented examination of structural and functional brain connectivity at previously impossible levels of spatial and temporal resolution. While this information has proven crucial to our understanding of normative variation in adult brain connectivity, little is known about the developmental processes through which this variation arises. In this project, we apply the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain develops. This work is conducted through a consortium of five sites (Harvard University, University of California at Los Angeles, University of Minnesota, University of Oxford, Washington University in St. Louis), with extensive complimentary expertise in human brain imaging and neural development and including many of the investigators from the original adult and pilot lifespan HCPs. This group will acquire, analyze, and publicly share approximately 1500 high quality neuroimaging and associated behavioral datasets on healthy children and adolescents from 5–21 years of age. This unique protocol is designed to provide rich, multimodal data on several biological and cognitive constructs that are of critical importance to health and well-being across this age range and allow a wide range of investigators in the community to test a host of crucial hypotheses about brain development and connectivity.

Microstructural and functional MRI signatures of brain alterations in patients with mucopolysaccharidosis

Principal Investigator:

Igor Nestrasil, MD, PhD (Department of Pediatrics)

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Collaborators:

Julie Eisengart, Phd, LP (Department of Pediatrics)

Abstract:

We intend to employ a non-invasive technique using brain magnetic resonance imaging (MRI) along with analysis of microstructural and functional MRI signatures of these regions to measure and determine the alterations and their impact on clinical variability in mucopolysaccharidosis (MPS) patients. The study aims to identify the neuronal and functional signatures in MPS patients who have been scanned longitudinally. To accomplish this aim, we have established MRI parameters for detection of abnormalities in myelin content, microstructural integrity, and functional connectivity in the brain of MPS patients. The study also aims to determine the role of myelin abnormalities in cognitive deterioration in MPS subjects by relating comprehensive neurocognitive assessments to their respective MRI outcomes.

Neurobehavioral mechanisms in tic suppression

Principal Investigator:

Christine Conelea, PhD (Department of Psychiatry)

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Collaborators:

Kathryn Cullen, MD (Department of Psychiatry), Kelvin Lim, MD (Department of Psychiatry)

Abstract:

The overall research objective of this project is to examine neurobehavioral mechanisms underlying tic suppression using an innovative methodology that integrates repetitive transcranial magnetic stimulation (rTMS) with an established behavioral tic suppression paradigm. TMS is a non-invasive procedure that temporarily increases or decreases cortical activity, which allows researchers to make inferences about the neurobiological underpinnings of a disorder. TMS has been used to examine the pathophysiology of tics by targeting the motor cortex node of the CSTC, which is involved in voluntary suppression of movement (primary motor cortex, M1) and involuntary urges to move (supplementary motor cortex, SMA). This work has primarily compared M1 and SMA functioning across discrete diagnostic categories (e.g., Tourette Syndrome (TS) vs. controls; TS vs. TS+ADHD) but has yet to focus on the relationship between motor cortex functioning and tics themselves. Direct examination of tics and urges after rTMS can be accomplished using an established behavioral paradigm developed to study the effects of context on tic suppression. The proposed study will examine the effect of 1hz active versus sham rTMS over SMA on tic frequency, suppressability, and urges in youth with chronic tics. Research linking this behavioral tic suppression paradigm with targeted examination of SMA activation will help clarify the neurobehavioral mechanisms underlying tic suppression.

Neurodevelopmental effects of fetal alcohol exposure (CIFASD)

Principal Investigator:

Jeff Wozniak, Ph.D., L.P. (Department of Psychiatry)

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Collaborators:

Bryon Mueller, Ph.D. (Psychiatry), Christopher Boys, Ph.D. (Department of Pediatrics), Kelvin Lim, M.D. (Department of Psychiatry)

Abstract:

The long-term aims of this research are to understand the neurobiological abnormalities that underlie cognitive and behavioral deficits in children with prenatal alcohol exposure. Prior research has clearly demonstrated that children with Fetal Alcohol Syndrome (FAS) have characteristic abnormalities in both the structure and function of their brains. Individuals with FAS have lower intellectual functioning, attention deficits, problems with memory/learning, and difficulties with organization/planning. Much less is known about brain structure and function in children who have a less severe diagnosis within the category of Fetal Alcohol Spectrum Disorder (FASD). This is the diagnostic term applied to those who have been exposed to alcohol prenatally and show some cognitive deficits but do not show all of the classic physical features of FAS (such as delayed growth and unusual facial features). We will use Magnetic Resonance Imaging (MRI) and neurocognitive tests to assess brain abnormalities in children with FASD compared to control participants.

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